Diabetes is a general term for disorders in man having excessive urine excretion as in diabetes mellitus and diabetes insipidus. Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. About 5% of all people suffer from diabetes. Since the introduction of insulin in the 1920's, continuous strides have been made to improve the treatment of diabetes mellitus. To help avoid extreme glycemia levels, diabetic patients often practice multiple daily injection therapy, whereby, for example, fast-acting insulin is administered with each meal and long-acting or intermediate-acting insulin is administered once or twice daily to cover the basal need.
In the treatment of diabetes mellitus, many varieties of insulin formulations have been suggested and used, such as regular insulin, isophane insulin (designated NPH), insulin zinc suspensions (such as Semilente®, Lente®, and Ultralente®), and biphasic isophane insulin. As diabetic patients are treated with insulin for several decades, there is a major need for safe and life quality improving insulin formulations. Some of the commercially available insulin formulations are characterized by a fast onset of action and other formulations have a relatively slow onset but show a more or less prolonged action. Fast-acting insulin formulations are usually solutions of insulin, while retarded acting insulin formulations can be suspensions containing insulin in crystalline and/or amorphous form precipitated by addition of zinc salts alone or by addition of protamine or by a combination of both. In addition, some patients are using formulations having both a fast onset of action and a more prolonged action. Such a formulation may be an insulin solution wherein protamine insulin crystals are suspended. Some patients do themselves prepare the final formulation by mixing a fast acting insulin solution with a protracted acting insulin suspension formulation in the ratio desired by the patient in question.
Human insulin consists of two polypeptide chains, the so-called A and B chains which contain 21 and 30 amino acid residues, respectively. The A and B chains are interconnected by two cystine disulphide bridges. Insulin from most other species has a similar construction, but may not contain the same amino acid residues at the same positions.
The development of the process known as genetic engineering has made it possible to prepare a great variety of insulin compounds being analogous to human insulin. In these insulin analogues, one or more of the amino acids have been substituted with other amino acids which can be coded for by the nucleotide sequences. All these compounds might be suitable to be combined with betaines according to the present invention.
Normally, insulin formulations are administered by subcutaneous injection. What is important for the patient is the action profile of the insulin formulation which is the action of insulin on the glucose metabolism as a function of the time from the injection. In this profile, inter alia, the time for the onset, the maximum value, and the total duration of action are important. A variety of insulin formulations with different action profiles are desired and requested by the patients. One patient may, on the same day, use insulin formulations with very different action profiles. The action profile requested is, for example, depending on the time of the day and the amount and composition of any meal eaten by the patient.
There is a big need for insulin formulations with different profiles of release of insulin. A patient may, during the day, use insulin formulations with different profiles of release. For example, the patient may, before a meal, use a fast-acting insulin formulation with no retarded action. Another patient may, before a meal, use a formulation having both a fast action and a retarded action. In such a formulation having both a fast action and a retarded action, the ratio between fast action and retarded action may vary considerably. Before a patient goes to sleep, the patient may use a long-acting insulin formulation. Some patients will, before they go to sleep, use a formulation having both a fast action and a retarded action.
It is a goal of the present invention to provide stable insulin/betaine pharmaceutical combinations and/or dosages forms suitable to meet patients' needs. Such insulin/betaine combinations are suitable for reducing the necessity of repeated administrations when rapidly and for long periods of time controlling blood glucose in a mammal.
Diabetic conditions are generally classified as either insulin-dependent diabetes mellitus (IDDM, Type I diabetes) or non-insulin-dependent diabetes mellitus (NIDDM, Type II diabetes). There are also less common clinical pathologies that are associated with diabetic conditions, such as gestational maturity-onset diabetes of youth (MODY), tropical diabetes secondary to chronic pancreatitis, diabetes secondary to pancreatic disease or surgery, and diabetes secondary to endocrinopathies.
The concept of combination therapy is well exploited in current medical practice. Treatment of pathology by combining two or more agents that target the same pathogen or biochemical pathway sometimes results in greater efficacy and diminished side effects relative to the use of the therapeutically relevant dose of each agent alone. In some cases, the efficacy of the drug combination is additive (the efficacy of the combination might be approximately equal to the sum of the effects of each drug alone), but in other cases the effect can be synergistic (the efficacy of the combination is greater than the sum of the effects of each drug given alone). In real medical practice, it is often quite difficult to determine if drug combinations are additive or synergistic.
For most diabetic patients, treatment involves some form of insulin therapy. In addition, IDDM patients may receive a biguanide (e.g., metformin) to enhance the insulin utilization by peripheral tissues. NIDDM patients are often treated with a combination of insulin, a sulfonylurea (to enhance insulin production in the pancreas) and a biguanide or glitazone (to enhance insulin sensitivity by peripheral tissues). For example, the improved utility of a glitazone in combination with a sulfonylurea was recently demonstrated in human clinical trials (see, WO 98/36755). Recently, two glitazone compounds (rosiglitazone and pioglitazone) were approved in the United States for the treatment of NIDDM patients in combination with metformin.
A variety of antidiabetic compounds are known. For example, sulfonylureas are a group of drugs that induce hypoglycemia by stimulating insulin release from the pancreas. Generally, sulfonylureas have found wide utility in the treatment of NIDDM. Their efficacy is decreased in IDDM because of the inherent inability of the patient to produce insulin. Adverse reactions to sulfonylureas occur in a fraction of patients, particularly the elderly. One of the most severe side effects is hypoglycemia and coma. Other side effects include nausea and vomiting, cholestatic jaundice, agranulocytosis, cardiovascular mortality, aplastic and hemolytic anemias, generalized hypersensitivity reactions and dermatological reactions.
Biguanides are another group of drugs, first introduced in the mid 1950's that have shown efficacy in the treatment of hyperglycemia by mechanisms that are not well understood. The best known agents of this type include metformin, phenformin and buformin. Unlike the sulfonylureas, metformin does not induce release of insulin from the pancreas. It is thought that its effects are mediated by increasing insulin activity in peripheral tissues, reducing hepatic glucose output due to inhibition of gluconeogenesis and reducing the absorption of glucose from the intestine. Side effects associated with the use of biguanides include lactic acidosis, diarrhea, nausea, and anorexia. These agents are often given in combination with drugs that increase the output of insulin from the pancreas, such as the sulfonylureas, which sometimes results in greater efficacy and/or the ability to use lower doses of the drugs, with an improved side effect profile.
More recently, the glitazones have been introduced and are widely used in the treatment of NIDDM. These agents, also known generically as thiazolidinediones, such as troglitazone, rosiglitazone and pioglitazone, are thought to work by increasing the sensitivity of peripheral tissues, such as skeletal muscle, towards insulin. They are often used in combination with insulin or other agents, such as the sulfonylureas, that enhance the release of insulin from the pancreas. A number of side effects have been described during the clinical evaluation of these agents, including hepatotoxicity, organomegaly, edema, anemia and body weight gain. While hepatotoxicity may be the most acutely life-threatening of these conditions, it does not appear in a large percentage of the patient population. On the other hand, the increases in body weight gain associated with chronic glitazone treatment are generally perceived as worsening an already critical co-morbid condition in the majority of the diabetic patients, and may ultimately result in the loss of antidiabetic efficacy for this type of agent after chronic treatment.
Alpha.-Glucosidase inhibitors, such as acarbose, reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of intestinal brush border .alpha.-glucosidase. Inhibition of this enzyme slows the absorption of carbohydrates and the rise in plasma glucose that normally follows after a meal is blunted. Acarbose has shown some benefit in IDDM and NIDDM patients, but is often associated with dose-related malabsorption, flatulence and abdominal bloating.
Other types of agents that have found limited utility in treating diabetes include potassium channel antagonists such as repaglinide, and aldose reductase inhibitors such as zopolrestat and tolrestat. Still in the experimental stage, glucagon antagonists, activators of the retinoid-X receptor (RXR), activators of PPAR.alpha., activators of PPAR.delta. and anti-obesity agents are also being evaluated as potential antidiabetic agents.
In view of the foregoing, there remains a need in the art to provide more efficacious treatment for diabetic conditions and diabetic complications. Combination therapy treatments are needed that will reduce the amount of drugs taken, thereby decreasing side effects. Surprisingly it was found that combining the betaines, i.e. one or more compounds selected from one or more of betaines, lipidic betaines, betaine lipids, of the invention with insulin agents enhance their effectiveness, the duration of theirs effects while lessening their potential side effects. The concomitant uses of betaines with insulins agents permit to lower the amounts of the latter while augmenting their half-life. The present invention fulfils these and other needs.